Field of the Invention
The present invention relates to a pig for an atrioventricular block model, a monkey for an atrioventricular block model, a guinea pig for an atrioventricular block model, a method for allowing a pig, a monkey or a guinea pig to develop atrioventricular block, an evaluation method for evaluating development of atrioventricular block, an atrioventricular block model, and a method for producing the atrioventricular block model.
Description of the Related Art
Fingolimod (also called “FTY720”) [trade name: IMUSERA (registered trademark, product of Mitsubishi Tanabe Pharma Corporation (see “Therapeutic Drug for Multiple Sclerosis IMUSERA (registered trademark) capsule 0.5 mg” Pharmaceutical Interview Form, revised in April, 2012 (third edition)) or trade name: GILENYA (Novartis Pharma K.K.)) is a drug for multiple sclerosis targeting a sphingosine-1-phosphate receptor. At the 3rd DIA Cardiac Safety Workshop (May 28, 2012, Tokyo), Dr. Strnadova (Health Canada, Canada) reported that fingolimod was administered to 366 cases at a dose of 1.25 mg/day in a clinical trial (phase III) and the Holter electrocardiograms measured one day after the administration thereof show that 6.6% of the cases developed second-degree atrioventricular block (Mobitz type I or type II), 3.4% thereof developed advanced atrioventricular block (2:1 atrioventricular block) and 0.3% thereof developed third-degree atrioventricular block (complete atrioventricular block). Although the frequency of occurrence of complete atrioventricular block is quite low, fingolimod causes complete atrioventricular block one day after the administration thereof and has a risk of causing sudden death. Thus, fingolimod is quite dangerous and has problems to be solved rapidly.
Notably, the safety of fingolimod was evaluated in a non-clinical trial by administering fingolimod to experimental animals such as a mouse and a dog at a dose 10 times to 30 times greater than that for human, and as a result the occurrence of atrioventricular block was not reported in these animals but was confirmed for the first time when fingolimod was administered to human.
Also, it has been reported that prolongation of PR interval was not observed when administering sphingosine-1-phosphate to a rat (see Sugiyama A, et al., 2000, Jpn. J. Pharmacol., 82(4), pp. 338-342).
The atrioventricular block is a type of arrhythmia and includes first-degree atrioventricular block, second-degree atrioventricular block, advanced atrioventricular block, and third-degree atrioventricular block. The first-degree atrioventricular block is a state where PR interval is prolonged for 0.2 sec or longer in human. The second-degree atrioventricular block is further classified into Type 1 (Mobitz type I (also called “Wenckebach type”)) and Type 2 (Mobitz type II). The Wenckebach type is a state of repeating a pattern where PR interval is gradually prolonged and then QRS (ventricular contraction) is dropped. The Mobitz type II is a state where ventricular contraction is suddenly dropped without prolongation of PR interval. The advanced atrioventricular block is a state where atrial excitation is conducted to the ventricle at a frequency of only 2:1 (atrium:ventricle) or 3:1 (atrium:ventricle) or less. The third-degree atrioventricular block is a state where the atrium and the ventricle are moved independently of each other at their own individual rhythms.
Fingolimod is one example of a commercially available drug having a side effect of fatal ventricular arrhythmia which could not be predicted in its non-clinical trial. Similar to fingolimod, all immune regulators targeting a sphingosine-1-phosphate receptor have a risk that the occurrence of atrioventricular block is first confirmed although such a side effect of causing atrioventricular block was not confirmed in their non-clinical trials.
Therefore, at present, there has been a strong demand to predict development of atrioventricular block as a side effect at the stage of non-clinical trials, in order to eliminate possibility of sudden death caused by complete atrioventricular block and further develop an immune regulator capable of being conveniently administered to patients at their homes rather than under medial supervision.